Novel Platforms for Systematic Optical Control of Complex Neural Circuits In Vivo A key feature of neural circuits in the mammalian brain is their 3-dimensionality and geometric complexity. In order to understand how normal and pathological brain functions emerge from these complex circuits, we propose to discover new reagents and invent new devices capable of perturbing activity in these structures, in their true 3-D complexity, thus enabling us to understand the causal contribution of each of these circuits to neurological and psychiatric disorders, and to powerful functions of the brain such as sensation, emotion, cognition, and action. Using molecular sensitizers that we have developed, such as channelrhodopsin-2 and halorhodopsin, as well as new molecules that we plan to develop for powerful neural silencing of circuits (Aim 1), we can use light to turn neurons on and off, enabling rapid assessment of their function in intact circuits. However, to date it has not been possible to manipulate neural circuits in their 3-D complexity, in the intact brain. We will develop micromachined, custom-fabricatable structures and technologies capable of delivering light to arbitrary structures in the brain (Aims 2 and 3), thus enabling real- time parsing of how complexly-shaped neural circuits operate in the normal and abnormal brain. Our inventions may directly enable new therapies, by subserving a new generation of optical prosthetics capable of using light to treat neurological and psychiatric disorders. PUBLIC HEALTH RELEVANCE: The ability to parse out how complex, 3-D neural circuits - such as the curved hippocampus, or the distributed frontoamygdala projection - causally contribute to normal and pathological brain functions is essential for the understanding of how mental disorders such as drug addiction arise from corrupted neural circuits in the brain. Our proposal will yield the first reagents and devices capable of activating and silencing these structures in their true 3-D complexity, alone and in combination, thus enabling new understandings of how different brain structures and neural circuits, of complex anatomical circuit complexity, contribute to normal and aberrant brain function. In addition, our inventions may directly enable new therapies for improving human health, through translational work. 1